Multi-omics and network pharmacology approaches reveal the mechanism of action of KeKe tablet against post-infectious cough.

BACKGROUND: Post-infectious cough (PIC) refers to a persistent cough lasting longer than three consecutive weeks following an infection, despite the resolution of other symptoms and normal examination results. This common respiratory disorder significantly impacts patients' quality of life due to the ongoing coughing. The Keke tablet (KKP), an herbal medicine preparation, is frequently used as an over-the-counter (OTC) treatment for respiratory conditions. However, the mechanisms underlying KKP's efficacy are not yet fully understood. OBJECTIVE: This study aims to evaluate the therapeutic effects of KKP in treating PIC and to explore its potential mechanisms of action. METHODS: Rat models of post-infectious cough (PIC) were established through exposure to cigarette smoke, capsaicin nebulization, and intranasal instillation of lipopolysaccharide, followed by intragastric administration of Keke tablets (KKP). Hematoxylin and eosin (HE) staining assessed the morphology of trachea and lung tissues. Cytokine levels in serum and lung tissues were measured using ELISA kits. Immunofluorescence techniques were utilized to visualize neurotransmitters in airway and lung tissues. Network pharmacology, transcriptomic and proteomic analyses were conducted to explore the underlying mechanisms of KKP, while Western blotting estimated the expression levels of proteins involved in relevant pathways. RESULTS: KKP significantly improved the pathological damage in airways and lung tissues and enhanced lung function in rats with PIC. Treatment with KKP resulted in decreased concentrations of inflammatory mediators in both serum and lung tissues, alleviating inflammatory responses. Additionally, KKP effectively reversed neurogenic inflammation associated with PIC by enhancing neutral endopeptidase activity and reducing the levels of substance P and calcitonin gene-related peptide. Network pharmacology, transcriptomics and proteomics analyses indicated that KKP exerted its therapeutic effects by regulating inflammation-related pathways such as MAPK/NF-κB signaling pathway. Western blot analysis further confirmed that KKP activated this pathway, evidenced by reduced expression of p65-NF-κB and p-38 MAPK following KKP administration. CONCLUSION: Our findings highlighted the clinical potential of Keke Tablet in the treatment of post-infectious cough, and confirmed that Keke tablet improved cough symptoms by alleviating inflammatory response. MAPK/NF-κB signaling pathway is one of the potential pathways of Keke tablet in the treatment of post-infectious cough.